Friday, December 22, 2006

Looking for ways to fill up your Christmas holiday?

Then why not heed these shameless plugs for my friends? John Whitfield’s book In The Beat of a Heart is a fabulous read – one of the best science books of 2006, though it’s not received the UK push it deserves. If this doesn’t get shortlisted for next year’s Aventis Prize, there’s no justice. It explains the notion of metabolic scaling in biology – the idea that one can develop a unified view of life by considering the way energy requirements depend on size. Like Nick Lane’s Power, Sex, Suicide, it’s a timely reminder that there’s more to life than genes.

And if you’re in the Lincoln area, pay a visit to Lindsay Seers’ exhibition The Truth Was Always There, which explores connections between magic and alchemy, Lincoln cathedral, Robert Grosseteste, Temple Bruer and John Dee. This is part of an ongoing project by Lindsay, comprising five ‘biographical’ films that document a strange past and an obsession with becoming a human camera. There’s a forthcoming book, called (I think) Human Camera, that records these films and narratives. Yes, I admit that I’m a contributor – but that’s because I think it is a wonderful project. The exhibition runs until late January.

[This is the pre-edited version of my Crucible column for the February issue of Chemistry World.]

Life is pretty simple, when you come down to it. It’s a matter of shovelling stuff from one side of a wall to the other – the ‘stuff’ being hydrogen ions, and the wall a cell membrane. The biochemistry that follows from this is fearsome, but at root life is driven by piling up hydrogen ions and then letting them flow, like water released from a dam.

This imbalance of protons across a membrane creates a so-called protonmotive force. It is generated by proton pumps: proteins that can actively move protons ‘uphill, against a concentration gradient. They need energy to do that, and in the light-harvesting chloroplasts of plants that comes ultimately from sunlight, which sets an electron jumping between molecules. In our mitochondria the energy is generated by reactions that break down carbohydrates. In either case, the protonmotive force is used to power the enzyme ATP synthase, which rotates like a water wheel as it lets protons flow through, producing energy-rich ATP in the process.

So if that’s life in a nutshell, these proton pumps clearly need to be efficient and smooth-running pieces of molecular machinery. Even so, the ingenuity life displays in conducting and controlling the movement of protons is breathtaking.

That life exists in water is a boon from the outset – because one of the things water does that other liquids cannot is transport protons rapidly. The hydrogen ion travels faster than other small cations in water by hopping along hydrogen-bonded chains of water molecules: rather like a Newton’s cradle, a proton hits one end of the chain and almost at once (figuratively speaking) another proton pops off the other end. This hopping, called the Grotthuss mechanism after the nineteenth-century German scientist who proposed the basic idea, is exploited by biomolecules to shift protons. Some proteins, such as the light-powered bacterial proton pump bacteriorhodopsin and some cytochromes, are threaded by ‘water wires’, strings of water molecules that act as proton-conducting pathways.

A water wire also winds through the membrane protein aquaporin, which transports water across cell walls. But for aquaporin, letting protons through could be disastrous, as it would disrupt the delicate balance of pH and charge across the membrane. So it has to achieve the seemingly impossible feat of transporting water but not hydrogen ions. How it does so is still not fully clear, but one idea is that the water wire contains a defect: hydrogen-bonding to the amino-acid residues within the pore forces two waters in the chain to sit ‘back to back’, so that a proton can’t jump between them.

That would be an extraordinarily delicate feat of molecular manipulation. But it is possibly trumped by the latest revelation about why proton pumping works so well. Magnus Brändén of Stockholm University and his colleagues (Proc. Natl Acad. Sci. USA, doi:10.1073/pnas.0605909103) say that there are, in effect, little proton circuits written onto the surfaces of cell membranes that help guide protons from a transporter – a pump protein – to molecules that exploit the protonmotive force, such as ATP synthase. The image, then, is not that of a pump spouting out protons into the cytoplasm, where some gradually drift over to where they’re needed; instead, the protons pop out of the pump’s mouth and stick to the membrane before proceeding to hop across it. That way, fewer get lost.

In effect, then, the membrane lipids act as proton-collecting antennas – rather as accessory pigments serve as light-harvesting antennas to shunt light energy onto the photosynthetic reaction centre in photosynthesis.

This idea has been mooted for years, but Brändén and colleagues have pinned it down by looking at the protonation of a single fluorescein dye molecule embedded in the wall of liposomes (closed, cell-like assemblies of lipids). Protonation changes the dye’s fluorescence, and so fluctuations in its brightness can be related to the rate of proton exchange with the surroundings. The researchers show that this happens at a faster rate than would be expected if protons were just being exchanged with the water – so long as the lipid head groups can themselves be protonated. The lipids gather protons and pass them around.

It’s a reminder that molecular biology isn’t just about the cleverness of proteins and nucleic acids. Even the molecules often assumed to be just part of the background or the scaffolding, such as lipids and water, may have inventive roles to play.

Thursday, December 21, 2006

Mining the moon for all it’s worth

It's one of the curious characteristics of space exploration that the usual stringent hurdles for science news stories are nowhere to be seen. Whereas normally science reporters, enthusing breathlessly about new insights into, say, the origin of the universe, face an editor's dismissive "why do we care?", with space stories it is enough that someone did something or other up in space – hit a gold ball, say, or flew a shuttle mission without blowing up. True, if the story involves an unmanned spacecraft doing something like landing on a comet, then there might be some sales work to be done. But if there's a human inside, it doesn't much matter what he's up to – just stick it on the page.

That principle even extends to stuff that hasn't actually been done, but "will" be. We're going to send people to Mars! We're going to build a moon base! Yes, it's true that we've not even managed to finish off a useless piece of manned space junk floating inanely in Earth orbit, but look, we've learnt from our mistakes. (What we've learnt, it seems, is simply to make the claims bolder.) When something is going to be done in space, all critical faculties vanish. We're going to grow crystals there, or plants – and no matter whether that's really going to tell us anything worthwhile. And now the latest fad for which the media seems determined to fall hook, line and sinker is mining the moon for helium-3.

Helium-3, you see, is a wonderful clean fuel that will power our planet through nuclear fusion. Just a shuttle-load will power the USA for a year. And it's just waiting up there in the lunar soil for us to go and collect it.

Well actually, it isn't – we'd have to strip-mine vast areas of the moon to get at it. And while discussions of remote oil resources on Earth routinely have to run the gauntlet of hard-headed economical cost-benefit analysis, no one seems to care very much whether there is any justification for thinking that sending trucks to the moon to pick up this 'fuel' is really going to save anyone any money. All you have to do is talk about lunar helium-3 as a "cash crop".

And on top of that, there's the small difficulty that no one has ever produced energy from nuclear fusion in a commercially viable and sustainable way, and that even the most optimistic estimates put that goal 50 years distant. There's a good chance that it might not happen before 2100 (although making technological projections that far ahead is a bit pointless anyway).

The point is, of course, that these bogus utilitarian rationales are routinely trotted out in defence of a programme of human space exploration that is at root ideological. It's fine to believe that there is an intrinsic value in sending humans to other worlds (I happen to disagree, at least in the present state of affairs in space travel); but let's at least be honest about it. The magic word "resources" was invoked the last time I questioned the value of manned spaceflight (see here and here). But as I'd expected, when it came down to it what that meant was stuff like silicon – as though we are currently facing a silicon shortage here on our rocky planet.

So please – no more helium-3 as the justification for a moon base. That’s truly grasping at straws.

Monday, December 18, 2006

[This is a review of a book on the zoological art of Ernst Haeckel, to be published in Nature.]

Visions of Nature: The Art and Science of Ernst HaeckelOlaf BreidbachPrestel, Munich, 2006

When Nature’s millennial issue of 1900 listed the most important scientists of that age, there was only one German biologist among them: Ernst Haeckel, professor of zoology at the University of Jena. Reckoned to have been instrumental to the introduction of Darwinism in Germany, and responsible now for inspiring generations of scientists with his stunning drawings of the natural world, Haeckel still retains a claim to such recognition. He is perhaps most widely known now as the author and illustrator of Art Forms in Nature, a series of plates published between 1899 and 1904 that showed the marvellous forms and symmetries of creatures ranging from radiolarians to antelopes.

But few scientists of his time are more complicated. He was the archetypal German Romantic, who toyed with the idea of becoming a landscape painter, venerated Goethe, and was prone to a kind of Hegelian historical determinism that sat uncomfortably with Darwin’s pragmatic rule of contingency. Haeckel’s view of evolution was a search for order, systematization and hierarchy that would reveal far more logic and purpose in life than a mere struggle for survival. His most famous scientific theory, the so-called biogenetic law which argued that organisms retread evolutionary history as they develop from an egg (‘ontogeny recapitulates phylogeny’), was an attempt to extract such a unifying scheme from the natural world.

It can be argued that this kind of visionary mindset, when it creates strong preconceptions about how the world ought to be, does not serve science well. Haeckel supplies a case study in the collision between Romanticism and science, and that tension is played out in his illustrative work. Olaf Breidbach’s text to this lovingly produced volume never really gets to grips with that. It has a curiously nineteenth-century flavour itself, declining to grapple with the difficult aspects of Haeckel’s life and work.

Here, for instance, is a proposition: Ernst Haeckel’s influence on fin-du-siècle German culture was pernicious in its promotion of a ‘scientific’ racist ideology that fed directly into Nazism. That case has been made (by historian Daniel Gasman in particular), and while it can be debated, Breidbach goes no further than to admit that Haeckel became a ‘biological chauvinist’ during the First World War, and that ‘sometimes the tone of his writing was overtly racist.’ Breidbach admits that this is not a biography as such, but an examination of Haeckel’s visual heritage. Yet one could argue that Haeckel’s dark side was as much a natural consequence of his world view as was Art Forms in Nature.

The claim that Haeckel doctored images in order to make them fit with a preconceived notion of how biology works is harder to ignore in this context. Even in his own time he was accused of that (particularly by his rival Wilhelm His), and to my eye the evidence (see Nature410, 144; 2001 and Science277, 1435; 1997) looks pretty strong. But Breidbach skates over this issue, alluding to the allegations only to suggest that the illustrations ‘instructed the reader how to interpret the shapes of nature properly’. Well, indeed.

On the whole, though, Breidbach simply explains Haeckel’s reliance on image without assessing it. Haeckel’s extraordinary drawings were not made to support his arguments about evolution and morphogenesis; rather, they were the arguments themselves. He believed that these truths should be apparent not by analysing the images but simply by looking at them. ‘Seeing was understanding’, as Breidbach says. If that’s so, it places an immense burden of responsibility on the veracity of the images.

This is the nub of the matter. Breidbach suggests that Haeckel’s drawings are schematic and that, like any illustrator, Haeckel prepared them to emphasize what we are meant to see. But of course this means ‘what Haeckel has decided we should see’. Quite aside from whether he hid nascent appendages that challenged his biogenetic law, consider what this implies for the plates of Art Forms in Nature. They are some of the most beautiful illustrations ever made in natural history – but it seems clear now that Haeckel idealized, abstracted and arranged the elements in such a way that their symmetry and order was exaggerated. They are pictures of Platonic creatures, the ideal forms that Haeckel intuited as he gazed into his microscope. Their very beauty betrays them. They are, as Breidbach says (but seemingly without critical intent), ‘nature properly organized.’ In this way ‘the labour of the analyst was replaced by the fascination of the image’. Absolutely – for ‘fascinate’ used to mean ‘bewitch’.

It is not as if Haeckel did not have the alternative of photography – for microphotography was used as early as the 1850s. Breidbach recapitulates the arguments against an over-reliance on the veracity of photography (these ideas have been much discussed by cultural critics such as Vilém Flusser), pointing out that what one sees is determined by the technology. That is true, and it is apt to give photography a false authority. But are hand-drawn images really any better – let alone those rendered with such apparent skill and realism that their schematic nature is disguised? Indeed, Haeckel felt compelled in 1913 to publish Nature as an Artist, a series of photographs of his subjects which, he said, demonstrates that ‘there can be no talk of reconstruction, touching up, schematisation or indeed forgery’ in his drawings of the same. It was a remarkable work in its own right, but leaves us wondering why Haeckel did not use photos in the first place.

Another danger of such imagery is that it is prone to reflect the artistic styles of the day. Haeckel’s drawings fed into the florid, nature-inspired designs of the Art Nouveau and Jugendstil schools – but he was more influenced than influence. His medusae look like William Morris prints precisely because they have had that visual aesthetic imprinted on them. Breidbach says that for Haeckel, as for Goethe, ‘aesthetics is the foundation of his view of nature.’ But is that a good thing? As Ernst Gombrich has pointed out, artistic styles create unconscious biases and errors: when Gombrich speaks of the artist who ‘begins not with his visual impression but with his idea or concept’, it might as well be Haeckel he is talking of. And what happens when the cultural aesthetic moves on – does nature have to follow suit? Breidbach points out that, by using the visual language of his age, Haeckel helped to make science accessible to the public. But 20 years later, modernism had rendered his arabesque style old-fashioned.

As director of the Ernst Haeckel Museum at Jena, Breidbach has unequalled access to Haeckel’s notes and sketchbooks, and he makes good use of them. But perhaps for that very reason he felt unable to dig too deeply into the problematic areas his subject raises. (Haeckel is clearly still very much a legend at Jena, where his brain was cast in silver.) So although this is undoubtedly a gorgeous book, and the questions it raises are fascinating, I can’t help feeling that it represents an opportunity missed.

Thursday, December 14, 2006

Tainted by association?[This is the pre-edited version of my latest muse column for news@nature.]

Richard Doll's links with industry are disconcerting but hardly scandalous. And they don't make him a villain.

Few things will polarize opinion like the defamation of a recently deceased and revered figure. So the tone of the debate (here and here and here and here) that has followed the accusation that Sir Richard Doll, the British epidemiologist credited with identifying the link between smoking and lung cancer in the 1950s, compromised the integrity of his research by receiving consultancy payments from the chemicals industry, should surprise no one.

On the one hand, the disclosure of Doll's contracts with the likes of Monsanto and Dow Chemicals have provoked howls of outrage and accusations that his studies of purported links between the companies' products and cancer were nothing less than a cover-up. Much of this is crude conspiracy-theorizing; but there are also more weighty critics. Andrew Watterson, a professor of occupational and environmental health at the University of Stirling in Scotland, has said that "Doll's work… has limited the capacity of the UK over decades to take action on occupational and environmental carcinogens as quickly as it should have… His lack of transparency on and financial relationship with companies have seriously damaged the credibility of aspects of his research."

On the other hand, voices that will be no doubt dismissed by Doll's attackers as those of the 'establishment' have risen to defend his reputation. An editorial in the Times calls the charges "a cheap shot" made by "grave robbers". This, the newspaper intones gravely, is "a sad act of character assassination by people who should know better." Several leading UK scientists have written to the Times saying that "we feel it is our duty to defend Sir Richard's reputation and to recognise his extraordinary contribution to global health."

The situation is perhaps best exemplified by a leader headline in the Observer newspaper: "Richard Doll was a hero, not a villain." All of which brings to mind the comment of Brecht's Galileo: "unhappy is the land that needs a hero."

Unhappy we are indeed, if we cannot accommodate in our pantheons the complexities of real people. And while the collaborations of academe and industry certainly create tensions and problems, it achieves nothing to pretend that they ought not to exist.

Doll's consultancy work is not immune to criticism even by the standards of his time. But the suggestion that his research is invalidated, and his character besmirched, by such conflicts of interest (as they would now certainly be regarded) is one that smells of piety rather than an evaluation of the facts.

Here, then, is the case for the prosecution. Doll proclaimed that Monsanto's Agent Orange posed no carcinogenic hazard while receiving consultancy fees of $1000-1500 a day from the company for nearly 30 years. He compiled a review on behalf of ICA, Dow Chemicals and the Chemical Manufacturers' Association in their defence against claims of cancer induced in workers by exposure to vinyl chloride, for which he was paid £15,000. (Monsanto was also a big producer of vinyl chloride). And he argued that there was little basis for the idea that asbestos is a major health risk, while pursuing a long-term consultancy relationship with the UK's leading asbestos manufacturer Turner & Newall, which later donated £50,000 to set up Green College in Oxford, a medical school of which Doll was a founder and the first warden.

All of this would indict any researcher today who failed to declare such conflicts of interest. Doll was in fact rather inconsistent about such declarations – he made no secret of some of his links to industry, but the Monsanto connection was not disclosed until a court case over vinyl chloride in 2000. In any event, until the 1980s there was no expectation that academics should make this sort of paid work public, and so no reason to expect Doll to have been systematic about doing so.

That is one of the main lines of defence for Doll's supporters: it is absurd to judge him by today's standards, a notorious way of vilifying historical figures and events. It's a fair point, although we have to remember that we're talking here about the 1980s, not the nineteenth century. It doesn't take a great deal of insight to see that being paid by a company while assessing their products is not ideal.

Yet there is no obvious reason to regard this as venal or cynical on Doll's part. Using contract money to help set up a college does not seem particularly blameworthy. Doll donated other fees to charities such as the Medical Foundation for the Victims of Torture.

He gives every impression of being a man conducting his business in an environment that had not thought very hard about the proprieties of industrial research contracts. If he did not think too hard about it either, that does not make him a villain.

And he seems very much a man who knew his own mind. Overcoming industry's resistance to the link between smoking and cancer is hardly the act of someone in the pocket of corporations. Yet his scepticism about the effects of secondary smoking speaks of a man who was not turned into an ideologue by his conclusions.

On this count, we must remember that no evidence has been presented that Doll's conclusions were biased by his contracts. It's hard to see how that could be established either way; but certainly it is unfair to turn Doll into a yes-man bribed by industry.

Indeed, if anything, the affair has served to remind us how manipulative these industries could be. Peto says that Doll came under pressure (which he resisted) from the asbestos manufacturers not to publish any evidence of the harmful effects of their product. They claimed it would damage the national interest by undermining this important industry, and even threatened legal action. The Asbestosis Research Council, founded by Turner & Newall and others in 1957, has been accused of suppressing evidence of the dangers of asbestos, for example by vetting and censoring research on the topic [1].

A curious aspect of this whole business, not mentioned at all in media reports, is that it is all yesterday's news anyway. Doll's links with industry were reported by British newspapers after being discussed in an article published online on 3 November by the American Journal of Industrial Medicine [2]. But the information in that article on Doll's connections with Monsanto, Dow, Turner & Newall and others had all been documented in 2002 by one of the authors, Martin Walker [3]. In that latter paper, Walker states that Doll "has never made any secret of the fact that he has been funded by industry for specific research projects."

Quite aside from demonstrating the media's ability to generate its own content, this fact is notable because the American Journal of Industrial Medicine paper aims not to denigrate Doll but to call for a tightening of policies governing disclosures of interest today. There's still plenty of work to be done (see here and here) in that respect. We should recognise the shortcomings of the past, and move on.

Monday, December 04, 2006

Looking for Turing’s fingerprints

Here is the pre-edited version of my Crucible column for the January 2007 issue of Chemistry World.There’s considerably more on this issue in the forthcoming reworking of my 1999 book The Self-Made Tapestry. OUP will publish this as a series of three books, probably beginning in late 2007.

How did the leopard get its spots? Recent research supports an idea first suggested by legendary code-breaker Alan Turing.

After another long time, what with standing half in the shade and half out of it, and what with the slippery-slidy shadows of the trees falling on them, the Giraffe grew blotchy, and the Zebra grew stripy, and the Eland and the Koodoo grew darker, with little wavy grey lines on their backs like bark on a tree trunk; and so, though you could hear them and smell them, you could very seldom see them, and then only when you knew precisely where to look.

Kipling’s Just So story of how the animals of Africa obtained their distinctive marking patterns is a fine example of Lamarckism – the inheritance of environmentally acquired characteristics, in this case via what seems to be a kind of tanning process imprinted with the shadows of trees. But the explanation that his contemporary biologists would have offered, invoking Darwinian adaptation (the markings being assumed to serve as camouflage), was arguably little more than a Just So story too. It explained why a marking pattern, once acquired, would spread and persist in a population, but it could say nothing about how such a pattern came to be, either in evolutionary terms or during the embryonic development of a particular zebra, giraffe or koodoo.

It seems clear that this is not merely a genetic painting-by-numbers: the markings on two animals of the same species are recognizably alike, but not identical. How do the melanin pigments of animal pelts get distributed across the embryonic epidermis in these characteristically blotchy ways?

The favoured explanation today invokes a mechanism proposed in 1952 by the British mathematician Alan Turing, two years before his suicide by cyanide. Turing is best known for his work on artificial intelligence and the concept of a programmable computer, and for his wartime code-cracking at Bletchley Park. But his paper ‘The chemical basis of morphogenesis’ was something else entirely. It was an attempt to explain how the development of a body plan kicks off.

The fundamental question is how a spherical ball of cells ends up as a shape in which different cells, tissues and appendages are assigned to different locations. How does the initial spherical symmetry get broken? Turing’s comment reminds one of the old joke about physicists over-simplifying biology: “a system which has spherical symmetry, and whose state is changing because of chemical reactions and diffusion, will remain spherically symmetrical for ever… It certainly cannot result in an organism such as a horse, which is not spherically symmetrical.”

Turing proposed a set of differential equations which explained how molecules determining cell fates, called morphogens, might diffuse through a spherical body and induce (bio)chemical processes. Such a scheme is now called a reaction-diffusion system. The patterning results from competition between an autocatalytic reaction, which amplifies random chemical inhomogeneities, and diffusion, which smoothes them out. Turing’s calculations performed by hand (his notion of a digital computer was then barely realized) showed that patchiness could emerge. But it wasn’t until 1972 that Hans Meinhardt and Alfred Gierer in Germany clarified the essential ingredients of Turing’s model. The chemical patterns arise in the presence of an autocatalytic ‘activator’ molecule, and an inhibitor molecule that suppresses the activator. If the inhibitor diffuses more rapidly than the activator, then the concentration of activator is enhanced over short distances but lowered by the inhibitor over longer distances. This gives rise to islands of activator surrounded by regions where it is suppressed.

Calculations showed that this ‘activator-inhibitor’ mechanism could create orderly patterns of spots and stripes, more or less equally sized and equidistant. That brought to mind the leopard’s spots and the zebra’s stripes. But is such a system anything more than a pretty mathematical fiction? That wasn’t clear until 1990, when a team led by Patrick De Kepper at the University of Bordeaux identified the first chemical Turing pattern, using a reaction that, when well mixed, oscillated between yellow and blue states. This was closely related to the Belousov-Zhabotinsky (BZ) reaction, which was known since the 1960s to generate travelling chemical waves. The BZ reaction is a reaction-diffusion system, but does not itself produce stationary Turing patterns, because the relative diffusion rates of the reactants don’t fit Turing’s model.

Are patterns in the living world really made this way? Theoretical activator-inhibitor systems have now been able to provide very convincing mimics of a wide range of animal markings, from the reticulated mesh of the giraffe’s pelt to the crescent-shaped rosettes of the leopard and jaguar, the spots of the ladybird and the stripes of the zebrafish. All this looks plausible enough, but the clinching proof – the identification of diffusing morphogens responsible for pigmentation – has yet to be obtained.

There does now seem to be good evidence that chemical morphogens of the sort Turing envisaged act in biological development. Several proteins belonging to the class called transforming growth factor b proteins seem to act this way in fly and vertebrate morphogenesis, signalling the developmental fate of cells as they diffuse through the embryo.

But does anything like Turing’s mechanism act to shape embryos beyond the question of marking patterns, as Turing suggested? In general, embryogenesis seems more complex than that, operating under close genetic control. However, Thomas Schlake and colleagues at the Max Planck Institute of Immunobiology in Freiburg have very recently discovered that there is at least one other biological patterning process that apparently uses the activator-inhibitor mechanism. They have found that the follicles of mouse hair are positioned in the epidermis by the protein products of two classes of gene, called WNT and DKK. The former appears to take the role of activator, inducing follicle formation, while several variants of DKK proteins act as inhibitors1.

Hair and feather positioning has long been suspected as an example of a Turing pattern – the equidistant, roughly hexagonally packed patterns are just what would be expected. Schlake and colleagues have made that case by looking at how over-expression of WNT and DKK alters the follicle patterns on mutant mice, showing that these match the predictions based on an activator-inhibitor model. It is probably the best reason yet to think that Turing’s intuition was sound.